Despite increasing negative attitudes towards smoking and intensified public campaigns and legislation against smoking, virtually no further reduction in smoking has occurred in this country during the 1990's. According to the 1996 National Household Survey on Drug Abuse, an estimated 68.8 million Americans used tobacco products. Therefore, tobacco is one of the most widely abused substances. Many years of twin and family studies provide strong evidence for a genetic component to nicotine dependence. The heritabilities for nicotine dependence, estimated from twin, family and adoption studies, are in the range of 0.28 to 0.84, with a mean heritability of 0.53. Nicotine can increase dopamine release in the nucleus accumbens and the ventral tegmental area regions implicated in the rewarding properties of other addictive drugs. Taken together, these studies of heritability and the neurochemical basis for the rewarding properties of nicotine provide strong evidence that certain aspects of smoking are influenced by genetic factors. We hypothesize that a group of susceptibility genes increases vulnerability to nicotine dependence and that these can be detected by using a combination of a two-stage genome-wide screening and candidate gene approaches. In the first stage of genomic screening, approximately 1600 subjects from 400 nuclear families recruited equally from Caucasian and African American populations will be genotyped by 218 microsatellite markers spaced at approx. 20 cM throughout the genome, followed by model-free sib-pair linkage analysis. The potential regions of interest (P greater than 0.03) will be subjected to second stage genomic analyses by genotyping more markers (i.e., 2-5) on both sides of the region and by searching candidate genes within these regions. The same DNA samples will also be used for family-based association studies between the nicotine dependence and 10 plausible candidate genes, that are related to dopamine reward pathways or nicotine metabolism. The TDT or its variants will be used to test the significance. We expect that the completion of the proposed studies in this application will advance our understanding of genetic influences on nicotine dependence and may eventually allow targeting of novel prevention strategies to individuals at risk.